One of the most significant concerns with treatment of wounds is infection. Infected wounds delay the wound healing process and increase hospitalization time. Wound infections often lead to secondary infections, amputations, and even death. The prevalence of antibiotic-resistant bacteria is an especially serious problem for treating wound infection. In fact, through extensive long-term use, most antibiotics actually generate resistant bacteria.
One type of wound prone to infection are those associated with diabetes, including diabetic foot ulcers, the chronic wounds which often develop in diabetic patients. Wounds resulting from diabetic complications are prevalent. Diabetes can involve peripheral neuropathy, and increase the likelihood that infected wounds will not be treatable with systemic antibiotics. It may take several months for an ulcer to heal, placing the patient at risk of re-infection and new infections, including risk of bone infection (osteomyelitis) and/or progressive gangrene. Diabetes, generally, and diabetic foot infection, specifically, are the top causes of non-traumatic leg amputations in the developed world, and foot ulcers are now the most frequent cause of diabetes-related hospitalizations. Thus, wound infection is a major burden to both the patient and the healthcare system.
Systemic antibiotic treatments are often used to treat wound infection. However, systemic therapy often leads to several side effects, particularly in diabetic patients who generally have compromised kidney and liver function. In addition, systemic therapy often leads to the risk of insufficient tissue penetration, due to the impaired blood supply at the wound site. Most available systemic antibiotics generate resistant bacteria through extended use. Thus, an effective topical therapy is often preferred as a route of administration for the delivery of an antibiotic agent to a wound.
Pexiganan is a broad-spectrum antimicrobial peptide for topical administration. It has antimicrobial activity against Gram-positive and Gram-negative organisms that commonly infect skin and soft tissue. Pexiganan has the benefit of a low potential for induction of resistance and no cross-resistance with existing therapeutic antibiotics, as a consequence of its mechanism of action. However, a stable topical pexiganan composition has been very difficult to formulate and is not presently available.
Peptides are often challenging to formulate as they exhibit chemical instability, adopt multiple conformations, tend to self-associate and also exhibit complex physical instabilities, especially in topical form. Both chemical and physical stability are critical to an effective and commercial pharmaceutical formulation. An unstable formulation results in loss of potency and poor quality and patient compliance. Topical formulations, especially, must remain stable in the container while stored long term and then when applied to the skin. Thus, there remains a need for a dosage form for the topical administration of pexiganan, which provides effective treatment of wound infection, and which remains chemically and physically stable over a long storage term.